ADRA2A

Adrenoceptor alpha 2A (ADRA2A) is a member of Alpha-2-adrenergic receptors. These receptors have a critical role in regulating neurotransmitter release from sympathetic nerves and from adrenergic neurons in the central nervous system. Alpha-2-adrenergic receptors modulate functioning of major neurotransmitters like noradrenaline, serotonin and dopamine. The single nucleotide polymorphism in ADRA2A, -1291 C>G has been associated with severity of attention-deficit/hyperactivity disorder (ADHD) inattentive symptoms in clinical samples of ADHD patients with a combined type. This variant is also associated with a favorable response to methylphenidate in ADHD patients, inattentive type. Dexmethylphenidate is a potent stereoisomer of methylphenidate and it is expected that similar genetic effect of ADRA2A variants might also influence treatment response to dexmethylphenidate.

ANKK1/DRD2

Dopamine, a key neurotransmitter that controls cognition, emotion, locomotor activity and other endocrine functions, exerts it action by binding to five different receptors including the dopamine D2 receptor (DRD2). Dysregulation of dopaminergic signal transmission is found in many pathological conditions such as Parkinson’s disease and schizophrenia and compounds that act as DRD2 agonists or antagonists are used to treat these conditions. Both therapeutic and adverse events of several antipsychotics result from their high affinity to antagonize DRD2.

COMT

Catechol-O-Methyltransferase (COMT) is an enzyme responsible for the metabolism of catecholamines and catechol- estrogens in both the central nervous system and other organs. Dopamine is cleared mainly by COMT in the frontal cortex and a reduced activity of this enzyme results in higher synaptic levels of dopamine, which affects prefontal cortex cognitive response to certain drugs. A single nucleotide polymorphism of the COMT gene produces an amino acid change from valine to methionine (Val158Met) and reduces the enzyme activity by 3 to 4 fold.

CYP2B6

The Cytochrome P450 2B6 (CYP2B6) is involved in the metabolism of 4% of clinically important medications. This enzyme is highly polymorphic and to date, 37 different variants have been identified. The CYP2B6 assay identifies some common variants that are associated with variability in enzyme activity. CYP2B6 plays a role in the metabolism of the following drugs: Artemisinin, Bupropion (Wellbutrin), Cyclophosphamide (Cytoxan), Efavirenz (Sustiva), Ketamine (Ketalar), Meperidine (Demerol), Methadone (Dolophine), Nevirapine (Viramune), Propofol (Diprivan) and Selegiline (Eldepryl). The impact of CYP2B*6 polymorphism on the pharmacokinetics as well as the clinical response have been studied in patients taking methadone, bupropion and efavirenz. Limited evidence exists regarding the clinical impact of other polymorphisms. Inhibitors or Inducers of CYP2B6 enzyme may modify its activity and change the patient’s metabolizer status. This can result in drug-drug interactions when a drug substrate is prescribed with known CYP2B6 inhibitors or inducers.

CYP2C8

The cytochrome P450 enzyme 2C8 (CYP2C8) is responsible for the biotransformation of 5% of currently used drugs that undergo phase I hepatic metabolism. This enzyme is responsible for the oxidative metabolism of important pharmacological and toxicological implications for antidiabetic agents, paclitaxel, antidiabetics, antimalarial agents, thiazolidinediones, chemotherapeutic taxanes, and nonsteroidal anti-inflammatory drugs (NSAIDs). There is substantial evidence linking the CYP2C8 polymorphisms to variability in the pharmacological and safety profiles of the anticancer drug paclitaxel (Taxol, Abraxane, Onxol). Paclitaxel, a commonly used chemotherapy drug, is associated with a variety of severe side effects, including the development of sensory peripheral neuropathy that can progress to irreversible loss of manual dexterity and balance. This toxicity is multifactorial but is has been shown to be correlated with paclitaxel exposure. Individuals carrying the reduced function allele CYP2C8*3 have a decreased capacity to eliminate this medication and are at increased risk of paclitaxel-induced peripheral neuropathy. CYP2C8 also plays a critical role in the biotransformation and elimination of structurally diverse drugs such as enzalutamide (Xtandi), rosiglitazone (Avandia), pioglitazone (Actos), repaglinide (Prandin), ibuprofen (Advil, Midol, NeoProfen, Motrin, Caldolor, Ibu), treprostinil (Tyvaso) and montelukast (Singulair).

CYP2C9

The cytochrome P450 2C9 (CYP2C9) is involved in the metabolism of 15% of clinically important medications. This enzyme is highly polymorphic and to date, 30 different variants have been identified. The CYP2C9 assay identifies some common variants that are associated with variability in CYP2C9 enzyme activity, which has important pharmacological and toxicological implications for anticonvulsants, anticoagulants and certain antidiabetics. CYP2C9 plays a role in the metabolism of the following psychotropic drugs: fluoxetine (Prozac), Phenytoin (Dilantin), and Primidone (Mysoline). Several NSAIDs and Cox-2 inhibitors are substrates of CYP2C9 and patients with reduced CYP2C9 activity may have higher plasma levels of Celecoxib (Celebrex), Flurbiprofen (Ocufen), Piroxicam (Feldene), Meloxicam (Mobic). CYP2C9 plays a minor role in the elimination of Diclofenac (Voltaren), Sulindac (Clinoril) and Naproxen (Aleve). Cardiovascular medications that are metabolized by CYP2C9 include warfarin (Coumadin), Fluvastatin (Lescol), Losartan (Cozaar) and Irbesartan (Avapro). Other important drugs metabolized by CYP2C9 include antidiabetics like Tolbutamide, Glibeclamide (Micronase), Glipizide (Glucotrol) and Nateglinide (Starlix). Inhibitors or Inducers of CYP2C9 enzyme may modify its activity and change the patient’s metabolizer status. This can result in drug-drug interactions when a drug substrate is prescribed with known CYP2C9 inhibitors or inducers.

CYP2C19

The Cytochrome P450 2C19 (CYP2C19) is involved in the metabolism of 10% of clinically important medications. This enzyme is highly polymorphic and more than 30 different variant alleles have been identified. The CYP2C19 assay identifies some common variants that are associated with variability in CYP2C19 enzyme activity, which has important pharmacological and toxicological implications for antidepressants, benzodiazepines, antiplatelets and proton-pump Inhibitors. There is substantial evidence linking the CYP2C19 polymorphisms to variability in the pharmacological and safety profiles of the following therapies used in psychiatric conditions and pain management: Amitriptyline (Elavil), Sertraline (Zoloft), Clobazam (Onfi), Citalopram (Celexa), Escitalopram (Lexapro), Diazepam (Valium), Imipramine (Tofranil), Carisoprodol (soma). CYP2C19 This plays a minor role in the elimination of Methadone (Dolophine). Cardiovascular medications that are metabolized by CYP2C19 include the prodrug Clopidogrel (Plavix), Propranolol (Inderal) and Cilostazol (Pletal). Proton-pump Inhibitors like Omeprazole (Prilosec), Esomeprazole (Nexium), Lansoprazole (Prevacid), Dexlansoprazole (Dexilant), pantoprazole (Protonix), are major substrates of CYP2C19. Inhibitors or Inducers of CYP2C19 enzyme may modify its activity and change the patient’s metabolizer status. This can result in drug-drug interactions when a drug substrate is prescribed with known CYP2C19 inhibitors or inducers.

CYP2D6

The Cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of 25% of clinically important medications. This enzyme is highly polymorphic and more than 100 different variants have been identified. The CYP2D6 assay identifies common variants that are associated variability in CYP2D6 enzyme activity, which has important pharmacological and toxicological implications for antidepressants, antipsychotics, opioids, beta-blockers and antiarrhythmics. There is substantial evidence linking the CYP2D6 polymorphisms to variability in the pharmacological and safety profiles of the following psychotropics: Desipramine (Norpramin), Imipramine (Tofranil), Amitriptyline (Elavil), Nortriptyline (Pamelor), Haloperidol (Haldol), Trimipramine (Surmontil), Venlafaxine (Effexor), Doxepin (Silenor), Aripiprazole (Abilify), Atomoxetine (Strattera), Duloxetine (Cymbalta), Risperidone (Risperdal), Clomipramine (Anafranil) and Pimozide (Orap). CYP2D6 polymorphisms have been shown to affect the pharmacological and safety profiles of the following analgesics: Codeine, Tramadol (Ultram), Hydrocodone (Vicodin). Codeine and tramadol are pro-drugs that need to be activated by CYP2D6. Poor metabolizers are at high risk of therapy failure when given codeine or tramadol. On the other hand, rapid metabolizers may experience increased toxicity when given standard dosage of codeine and tramadol. Because CYP3A4 is also involved in the metabolism of oxycodone, patients with abnormal CYP2D6 activity may still experience adequate analgesia when taking this drug. CYP2D6 polymorphism has been shown to affect dihydrocodeine (Synalgos-DC) pharmacokinetics and can potentially alter the response to this drug. Morphine, Oxymorphone (Opana), Hydromorphone (Dilaudid), Butorphanol (Stadol), Fentanyl (Duragesic), Buprenorphine (Butrans), Methadone (Dolophine), Morphine (Avinza) and Tapentadol (Nucynta) are not substrates of CYP2D6 and the patient’s response to these drugs is not expected to be affected by polymorphisms in this enzyme.

CYP3A4/CYP3A5

The cytochrome P450 3A4 and 3A5 (CYP3A4 and CYP3A5) account for 40-80% of total CYP in human liver and intestine, respectively. Most importantly, CYP3A enzymes metabolize 50% of commonly used drugs. CYP3A4 and CYP3A5 enzymes have overlapping substrate specificity and the contribution of CYP3A5 in the overall metabolism is smaller than the one for CYP3A4. The overall CYP3A metabolism status is expected to affect drugs that have a narrow therapeutic index. CYP3A4 and CYP3A5 genotypes can help identify patients with high or low overall CYP3A activity. Although these two enzymes metabolize many drugs, the response of only a few (like narrow therapeutic index drugs) is expected to change significantly by genetic polymorphisms. Fentanyl (Duragesic) is a narrow therapeutic drug that is mainly metabolized by CYP3A. There is limited evidence suggesting that the response to this drug is altered in individuals with abnormal CYP3A activity. The following drugs used in pain management and various psychiatric conditions are metabolized extensively by CYP3A: Fentanyl (Duragesic), Oxycodone (Oxycontin) and Buprenorphine (Suboxone), Carbamazepine (Tegretol), Quetiapine (Seroquel), Ziprasidone (Geodon), Alprazolam (Xanax), Midazolam (Versed), Triazolam (Halcion), Nefazodone (Serzone), Trazodone (Oleptro), Vilazodone (Vibryd), Zaleplon (Sonata) and Zolpidem (Ambien). CYP3A contributes to a small extent in the elimination of Methadone (Dolophine). Within the major therapeutic classes used in cardiovascular conditions, the following drugs are substantially metabolized by CYP3A: Atorvastatin (Lipitor), Simvastatin (Zocor), Lovastatin (Mevacor), Nifedipine (Procardia), Verapamil (Verelan), Nicardipine (cardene), Felodipine (Plendil), Nisoldipine (Sular),Clopidogrel (Plavix), Prasugrel (Effient), Ticagrelor (Brilinta), Cilostazol (Pletal), Amiodarone (cordarone), Quinidine (qualaquin), Disopyramide (Norpace), Losartan (Cozaar), Rivaroxaban (xarelto), Apixaban (Eliquis). CYP3A metabolism is highly sensitive to inhibition and induction when a patient is taking multiple drugs. Then occurrence of drug-drug interactions can have profound effects on the pharmacokinetics, the response and safety profiles of many CYP3A drug substrates.

DPYD

The dihydropyrimidine dehydrogenase (DPYD) gene encodes a key enzyme (DPD) involved in uracil and thymidine catabolism, and the formation of beta-alanine. Some common variants that are associated with variability in DPD enzyme activity, which has important pharmacological and toxicological implications for all fluoropyrimidine drugs used in the treatment of cancer. There is substantial evidence linking the DPYD polymorphisms to variability in the pharmacological and safety profiles of the following therapies used in the treatment of cancer: fluorouracil (Efudex, Adrucil, Carac, Fluoroplex), capecitabine (Xeloda), and tegafur (Uftoral). Decreased DPYD activity is associated with a greater than 4-fold risk of severe or fatal toxicity from standard doses of these fluoropyrimidine drugs.

GRIK4

The GRIK4 gene encodes the kainic acid-type glutamate receptor, a protein that belongs to the glutamate-gated ionic channel family. Glutamate functions as the major excitatory neurotransmitter in the central nervous system, and a disturbance in the glutamate system is found during depression. Mutations in GRIK4 may impact patients with major depressive disorder who take citalopram.

HTR2C

HTR2C gene encodes a receptor that responds to the endogenous neurotransmitter serotonin. Serotonin signaling regulates mood, anxiety, feeding, and many other behaviors, as well as dopamine and norepinephrine release in certain areas of the brain. Genetic variation in the HTR2C gene in known to be partially involved in pathogenesis of some psychiatric disorders and adverse effects of antipsychotic medications. The HTR2C assay identifies mutations that are associated with altered serotonin receptor expression and function, which has important pharmacological and toxicological implications for the use of antipsychotic medications, such as olanzapine, clozapine and risperidone. The HTR2C assay identifies mutations that lead to functional variability in serotonin receptor, which is associated with clinical response to antipsychotics. Other genetic and clinical factors may also influence a patient’s response to olanzapine, clozapine and risperidone.

MTHFR

Methylenetetrahydrofolate reductase (MTHFR) is involved in folate metabolism and is essential for the remethylation of homocysteine. Two common mutations in the MTHFR gene: 677C>T and 1298A> result in an enzyme with decreased activity, which is linked to increased plasma homocysteine levels (I.e. hyperhomocysteinemia). Mild to moderate hyperhomocysteinemia has been identified as a risk factor for venous thromboembolism and other cardiovascular diseases such as coronary heart disease and stroke. Other conditions in which hyperhomocysteinemia is found include recurrent pregnancy loss, placental infarction and birth defects. However, the causal role of MTHFR mutations in these conditions is not well established.

OPRM1

“Mu” opioid Receptors are the most important site of action of opioid drugs. Single polymorphisms in the human mu- opioid receptor (OPRM1) have been investigated for their role in human nociception, opiate efficacy and addiction.

SLCO1B1

The SLCO1B1 gene encodes a liver-specific transporter involved in the removal of endogenous compounds (bile acids, bilirubin) and drugs such as statins from the blood to the liver. Some variants of the SLCO1B1 gene result in a low-functioning protein, which impairs statin clearance and may lead to an increased risk of muscle pain, tenderness or weakness, called myopathy. Certain medications can potently inhibit SLCO1B1 causing clinically significant drug interactions.

TPMT

The thiopurine S-methyltransferase (TPMT) is involved in the metabolism of thiopurine drugs, as well as other aromatic and heterocyclic sulfhydryl compounds. This enzyme is highly polymorphic: 28 variant alleles have been identified. The TPMT assay identifies important variants that are associated with variability in TPMT enzyme activity. TPMT activity is a significant predictor of serious adverse drug reactions (myelosuppression) in patients treated with thiopurine drugs. There is substantial evidence linking the TPMT polymorphisms to variability in the pharmacological and safety profiles of the following therapies used in the treatment of acute lymphoblastic leukemia, autoimmune disorders (e.g., Crohn’s disease or rheumatoid arthritis), and organ transplant recipients: azathioprine (Imuran, Azasan, Azamun, Imurel), mercaptopurine (Purinethol), and thioguanine (Tabloid). TPMT plays a critical role in the inactivation and elimination of thiopurine drugs. All thiopurines are metabolized by an alternative “metabolic activation” process, resulting in the formation of cytotoxic metabolites such as 6-thioguanine nucleotides (6-TGN) and methyl-thioinosine monophosphate. Inhibitors of TPMT enzyme may modify its activity and change the patient’s metabolizer status. This can result in drug-drug interactions when a drug substrate is prescribed with known TPMT inhibitors.

UGT2B15*

Uridine diphosphate glucuronosyl transferases (UGT) are important metabolizing enzymes that catalyze the addition of glucuronic acid to various substrates, including drugs, hormones, flavonoids, and environmental mutagens. The UGT superfamily 2 is divided into two subfamilies, UGT2A and UGT2B. The UGT2B15 isoform is expressed in the liver and is involved in the metabolism of androgenic steroids, as well as drugs such as anxiolytics and NSAIDs. Interindividual variability in the rate of glucuronidation of drugs can contribute to altered risk for drug toxicity and disease susceptibility. Various factors may contribute to glucuronidation variability, including genetic polymorphisms and drug-drug interactions resulting from enzyme induction and inhibition. The presence of the UGT2B15*2 allele (253G>T) is associated with oxazepam and lorazepam exposures. Lower oxazepam and lorazepam clearances are observed in individuals carrying one or two copies of the UGT2B15*2 allele. This may result in increased levels of these two benzodiazepines and exaggerate their sedative effects. A closer monitoring for increased sedation in UGT2B15 intermediate and poor metabolizers is recommended when starting these patients on standard doses of oxazepam or lorazepam. UGT2B15 is partly involved in the elimination of other drugs such as acetaminophen, dabigatran, ezetimibe, phenytoin, and valproic acid. However, genetic polymorphism of UGT2B15 gene is not expected to affect the clinical outcome of these drugs to a significant extent.

VKORC1

The Vitamin K epoxide reductase complex, subunit 1 (VKORC1) is the target of anticoagulants. This enzyme is the rate-limiting step in the vitamin K cycle. Mutations in the VKORC1 gene results in variable expression levels of the VKORC1 enzyme and altered sensitivities towards anticoagulants. VKORC1 genotype defines three levels of clinical phenotypes, a high sensitivity, a moderate sensitivity and low sensitivity phenotypes towards warfarin a widely used anticoagulant. Therefore, VKORC1 variant testing is usually used in conjunction with CYP2C9 variant testing to optimize warfarin dosing and minimize the risks of bleeding or thrombotic complications.